| Project/Area Number |
16209036
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Radiation science
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| Research Institution | National Institute of Radiological Sciences |
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Principal Investigator |
RYUICHI Okayasu National Institute of Radiological Sciences, Heavy-Ion Radiobiology Research Group, Group Leader (50356135)
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| Co-Investigator(Kenkyū-buntansha) |
YAMADA Shigeru National Institute of Radiological Sciences, Charged Particle Therapy Hospital, Chief Doctor (80311380)
安藤 興一 独立行政法人放射線医学総合研究所, 重粒子医科学センター・粒子線生物研究グループ, 特別上席研究員 (00159526)
窪田 宣雄 茨城県立医療大学, 保健医療学部, 教授 (20046139)
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| Project Period (FY) |
2004 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥46,540,000 (Direct Cost: ¥35,800,000、Indirect Cost: ¥10,740,000)
Fiscal Year 2007: ¥11,050,000 (Direct Cost: ¥8,500,000、Indirect Cost: ¥2,550,000)
Fiscal Year 2006: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000)
Fiscal Year 2005: ¥10,400,000 (Direct Cost: ¥8,000,000、Indirect Cost: ¥2,400,000)
Fiscal Year 2004: ¥14,430,000 (Direct Cost: ¥11,100,000、Indirect Cost: ¥3,330,000)
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| Keywords | Radio-sensitization / Hsp90 inhibitor / 17AAG / DNA DSB repair / Homologous recombination repair / BRCA2 / siRNA / Rad51 / Homologous recombination repair / 放射線増感材 / DNA DSB修復 / 17-AAG / 放射線抵抗性 / non-homologous end joining / DNA-PKcs / アポトーシス / 癌細胞 / 正常細胞 / 非相同末端結合 / RNA干渉 / DNA ligase IV |
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| Research Abstract |
We performed two specific aims on this project. Results for the individual aim are described.
Aim 1) lb investigate Hsp90 inhibitors as effective radio-sensitizers which have much higher affinity for tumor cells than for normal cells. We showed that 17-AAG effectively radio-sensitized human tumor cells in vitro and in vivo, while normal cells were not affected by the drug. The cause of this sensitization was found out to be inhibition of DNA double strand break (DSB) repair by 17AAG. We also discovered that 17AAG affected the homologous recombination repair (HRR) pathway of DSB repair. Furthermore, the proteins influenced by this chemical were found out to be BRCA2 and Rad51. (Noguchi, et. al. 2006)
Aim 2) lb find an efficient strategy to specifically damage tumor cells, the inhibition of HRR repair mechanism was pursued; the HRR mechanism is known to be active only at late-S and G2 phases of the cell cyde. We used RNA interference technology to knockdown the expression of BRCA2 protein, a crucial molecule for HRR pathway. After efficiently knocking down the protein expression by transfecting tumor cells by BRCA2 small interference RNA (siRNA), significant radio-sensitization was observed in HeLa cells. The cause of this sensitization was found out to be DNA DSB repair inhibition and the HRR pathway was again affected by BRCA2 siRNA transfection in tumor cells. The radio-sensitization was also observed in animal zenograft model. (Yu, et. al. 2008)
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